The major research effort in my laboratory is in the catalytic antibody field. This unique area of protein engineering has the potential to create tailor-made biological catalysts for application in chemistry, biology, and medicine. Specifically, we are interested in understanding the structure-function relations that are involved in converting a natural receptor like an antibody into an unnatural enzyme-like catalyst. We rely on a number of experimental techniques including organic chemistry, kinetic and mechanistic enzymology, x-ray crystallography, and molecular-level approaches. We have created a novel catalytic antibody in our laboratory and solved the high-resolution three-dimensional structure of the antibody-transition state analog complex in collaboration with Robert Fletterick's group here at UCSF. The active site of this catalytic antibody is remarkably similar to the active site structure of the serine protease family of enzymes. We are currently conducting kinetic, mechanistic, site-directed mutagenesis, and further structural studies in an effort to understand how this novel catalysts functions and how more active variants of the antibody can be engineered. These studies may also illuminate the molecular pathways of convergent evolution of the serine proteases. We are also pursuing several synthetic organic chemistry projects aimed at understanding the basis of molecular interactions between small organic ligands and proteins. One project deals with the nuclear hormone receptors including the estrogen and thyroid receptors. Using both traditional synthetic methods and modern combinatorial methods, we have prepared novel compounds that act as both agonists and antagonists at the nuclear receptors. A second receptor-ligand system that we are studying is the thrombin receptor, which belongs to the seven trans-membrane G-protein-coupled receptor superfamily. The thrombin receptor is unique in this family because it uses its own N-terminus as the signal-transducing ligand. The thrombin protease cleaves the extracellular N-terminal tail, generating a new N-terminus which which activates the G-protein coupled signal transduction by binding to the ligand-binding domain of the receptor. The hexapeptide NH2-SFLLRN-CO2, corresponding to the new N-terminus generated from thrombin cleavage, functions as an agonist of the receptor. We are synthesizing conformationally constrained peptidomimetic analogs of the agonist peptide in an effort to understand the structure-function relations of agonist and antagonist action for the thrombin receptor. The Computer Graphics Laboratory will enable us to analyze the atomic level details of the protein-ligand structures that we study. These analyses will guide mutagenesis experiments as well as ligand design experiments aimed at drug discovery.